Implantable and non-invasive stimulators for gastrointestinal therapeutics

ABSTRACT

Systems and methods for implementation of a disposable miniaturized implant for treatment of Post-Operative Ileums (POI),a miniaturized implant for treating chronic GI dysmotility (e.g., dysphagia, gastroesophageal reflux disease (GERD), nausea, functional dyspepsia, blockage of transit, and gastroparesis, inflammatory bowel disease) and obesity, by providing electrical stimulation to the part of bowel going through surgery to expedite the healing process while recording the smooth muscle activities simultaneously, or providing stimulation on a treatment location of the GI tract or the branch of the vagus nerve. Systems and methods are also provided for non-invasive, transcutaneous stimulation of anatomy within the abdomen of the patient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to, and is a 35 U.S.C. § 111(a)continuation of, PCT international application number PCT/US2017/065917filed on Dec. 12, 2017, incorporated herein by reference in itsentirety, which claims priority to, and the benefit of, U.S. provisionalpatent application Ser. No. 62/433,122 filed on Dec. 12, 2016,incorporated herein by reference in its entirety. Priority is claimed toeach of the foregoing applications.

The above-referenced PCT international application was published as PCTInternational Publication No. WO 2018/111943 on Jun. 21, 2018, whichpublication is incorporated herein by reference in its entirety.

This application is related to PCT International Application No.PCT/US2016/063886 filed on Nov. 28, 2016 and published as WO 2017/091828on Jun. 1, 2017, incorporated herein by reference in its entirety, whichclaims priority to, and the benefit of, U.S. provisional patentapplication Ser. No. 62/260,624 filed on Nov. 29, 2015, incorporatedherein by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable

NOTICE OF MATERIAL SUBJECT TO COPYRIGHT PROTECTION

A portion of the material in this patent document may be subject tocopyright protection under the copyright laws of the United States andof other countries. The owner of the copyright rights has no objectionto the facsimile reproduction by anyone of the patent document or thepatent disclosure, as it appears in the United States Patent andTrademark Office publicly available file or records, but otherwisereserves all copyright rights whatsoever. The copyright owner does nothereby waive any of its rights to have this patent document maintainedin secrecy, including without limitation its rights pursuant to 37C.F.R. § 1.14.

BACKGROUND 1. Technical Field

The technology of this disclosure pertains generally to therapeuticstimulation systems and methods, and more particularly to systems andmethods for therapeutic stimulation in treatment of gastrointestinaldisorders.

2. Background Discussion

Gastrointestinal neuromuscular disorder (GND) is a set of disorderscharacterized by the absence or poor function of the intestinalmuscularis (IM), involving any segment of the gastrointestinal (GI)tract. GND may affect the enteric nervous system, smooth muscle cells,and/or the interstitial cells of Cajal (ICC), which are the pacemakercells in the GI tract, thus resulting in functional GI diseases anddysmotility. Patients with GND may present with dysphagia,gastroesophageal reflux disease (GERD), nausea, functional dyspepsia,blockage of transit, and obstruction of the GI tract (e.g.,gastroparesis), which accounts for 40% of GI tract illness that patientsseek health care for in gastroenterology clinics. The current limitationin the treatment of GND associated GI dysmotility is the lack ofunderstanding of the pathophysiology involving the neurons, ICC, andsmooth muscle cells combined with the paucity of effective medicationsthat can improve GI motility. The clinical alternative forpharmaceutically intractable GI dysmotility is usually the total orsubtotal resection of the affected GI segments.

On the other hand, GI dysmotility can also be transiently inducedthrough surgical operation (e.g., bowel resection surgery), leading topost-operative ileus (POI). POI leads to the inflammation of the bowelwall that occurs following abdominal surgery and its economic impact isestimated to be between $3/4 billion and $1 billion per year in theUnited States. Patients with POI manifest abdominal pain, nausea,vomiting, as well as the inability of coordinated propulsive mobilitywhile the current treatment is restricted to the spontaneous recovery ofthe patient.

POI is not only limited to patients receiving abdominal surgery. Thereare patients receiving open-heart surgery also reporting symptomssimilar to POI, possibly because the sympathetic and parasympatheticnerves governing the GI tack are affected by the surgery.

BRIEF SUMMARY

A primary premise of the system and methods disclosed herein is thatelectrical stimulation in the vagus nerve reduces the level of tumornecrosis factor (TNF), indicating the decrease of inflammation or thedirect stimulation on the enteric nervous system and smooth muscles toadapting GI motility. Thus, an aspect of the present technology is asystem and method configured to treat GI dysmotility throughelectrophysiological intervention by stimulating the bowel wall wherethe nerve ending of VN is located or the vagus nerve at the cervical orceliac branch. For the therapeutic treatment of POI that presents atransient GI dysmotility, the device performing stimulation is small andeasily/conveniently removable after a course of POI treatment; for thediseases associated with chronic GI dysmotility, the miniaturized devicecan be implanted permanently.

In one embodiment, an SoC implant of the present description targetsmotor function of GI tract smooth muscles, with versatilefunctionalities and highly compact form factor (<0.5 cm³ and <0.7 g) forvarious medical applications.

In another embodiment, anon-invasive, transcutaneous stimulation systemis provided for stimulation of anatomy within the abdomen of the patient

Further aspects of the technology described herein will be brought outin the following portions of the specification, wherein the detaileddescription is for the purpose of fully disclosing preferred embodimentsof the technology without placing limitations thereon.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

The technology described herein will be more fully understood byreference to the following drawings which are for illustrative purposesonly:

FIG. 1 shows a schematic side view of the gastrointestinal (GI)stimulation implant of the present description.

FIG. 2 shows a schematic side view of an alternative GI stimulationimplant.

FIG. 3 shows a schematic side view of an alternative GI stimulationimplant.

FIG. 4A through FIG. 4C show bottom views of an intraluminal device withvarying electrode configurations.

FIG. 5 is an image of a stimulation waveform for triggeringmuscle/neuron response and impedance/motility measurements in accordancewith the present description.

FIG. 6 is an image of grouped stimuli for triggering muscle/neuronresponse and impedance/motility measurement in accordance with thepresent description.

FIG. 7A shows a front view of ventral body anatomy with acupuncturepoints and the electrode array of the present description.

FIG. 7B shows a side view of the patient with the GI stimulation systemof the present description.

FIG. 8 is an enlarged side view of the electrode structure of thepresent description.

FIG. 9A is an image of a retarded stimulation waveform.

FIG. 9B is an image of a stepwise stimulus to mitigate stimulation edgeeffect according to the GI stimulation system and methods of the presentdescription.

FIG. 10A through FIG. 10D show various stimulation current injectionschemes in accordance with the present description (the arrow signindicates the direction of onset sequence of the stimulation). An 8×8electrode array is used as an example for illustration. FIG. 10A showsstimulated electrodes in an onset sequence of stimulation horizontallyfrom left to the right. FIG. 10B shows stimulated electrodes in adiagonal onset sequence of stimulation. FIG. 10C shows stimulatedelectrodes in a clockwise rectangular onset sequence of stimulation.FIG. 10D shows stimulated electrodes in a clockwise spiral onsetsequence of stimulation.

FIG. 11 is a schematic block diagram of a non-invasive stimulator inaccordance with the present description.

FIG. 12 is a schematic block diagram of the power management circuit forthe stimulator of FIG. 11.

DETAILED DESCRIPTION

A first aspect of the technology described herein is based on systemsand methods for implementation of a disposable miniaturized implant fortreatment of treating gastrointestinal dysmotility, including dysphagia,gastroesophageal reflux disease (GERD), nausea, functional dyspepsia,blockage of transit, and obstruction of the GI tract (e.g.,gastroparesis, post-operative ileus, inflammatory bowel diseases). Onefunction of the implant is to provide electrical stimulation to the GItract through direct stimulation on enteric nervous system/ICCs or thecercial and celiac branches of the vagus nerve. A second function of theimplant is to provide electrical stimulation to the part of bowel goingthrough surgery to expedite the healing process while recording thesmooth muscle activities simultaneously; the third function of theimplant is to reduce regulating GI motility through intestinalelectrical stimulation for treating obesity. A fourth function of theimplant is to record the pH value, pressure, transits time.Disposability of the implant is a key feature, as patients with POIwould be less willing to undergo anther surgery to remove the device.For other chronic disease, the device would be a permanent implant.

A second aspect of the technology described herein is based on systemsand methods for non-invasive, transcutaneous stimulation of anatomywithin the abdomen of the patient.

A. Disposable Gastrointestinal Stimulator

FIG. 1 through FIG. 3 show schematic side view of three differentgastrointestinal (GI) stimulation implants (10 a through 10 c,respectively) in accordance with the present description. GI stimulationimplants 10 a through 10 c preferably comprise disposable GI implantsthat are battery powered (preferably with a rechargeable battery) toperform current mode stimulation. The GI stimulation implants 10 athrough 10 c are implemented by heterogeneously integrating themicroelectronics (i.e., the system-on-a-chip SoC), the battery, theantenna, other passive/active surface mounted components, and theelectrode array into a single biocompatible package. In a preferredembodiment, the GI stimulation implants 10 a through 10 c electricallymodulate the gastrointestinal tract smooth muscles and the neuronsresiding in the muscularis externa to restore GI motility andinflammatory responses, as well as wirelessly record the GI motility bymeasuring the electrode-tissue impedance, pH value, transit time, andpressure. In another embodiment, the implants 10 a through 10 c areconfigured to electrically modulate the vagus nerve to regulateautonomic functions.

FIG. 1 illustrates a first configuration of a GI implant 10 a having abattery 24 placed on the bottom side of the printed circuit board (PCB)interposer 18 a. In this embodiment, the PCB interposer 18 a is alsoused as an antenna for wireless signal transmission and recording. Asubstrate 36 a comprising an electrode array 16 a is provided fordelivering GI stimulation. Electrode array 16 a may also be configuredas a cuff electrode (not shown) for nerve stimulation. In a preferredembodiment, the substrate 36 a comprises a flexible material, such aspolyimide, parylene, silicone, or PDMS, or the like, with a thicknessgenerally ranging from 5 um to 50 um. The flexible substrate 36 a alsoserves as a soft interposer board in which electrical connections aremade by deposition of metal bumps 28 (e.g., Pt, Pt black, Titanium,gold, etc.) at pads 34.

An SoC 12 is positioned underneath the flexible substrate 36 a such thatspecified openings (e.g., round shape or square shape openings) disposedthrough the flexible substrate 36 a expose the metal pads 32 of the SoC12 to the metallic bumps 28 other passive/active components 14 a. Theopenings on the substrate 36 a are aligned to the metal pads 32 of theSoC enable its operation. In one embodiment, Gold/alumina bumps 28 witha diameter from about 20 μm to about 50 μm are positioned on top of theopening to link the SoC 12 and the flexible substrate 36 a.

The SoC 12 sits on top of a PCB interposer 18 a, which has patternedmetal to serve as an antenna and an interposer for the connection withthe battery 24. The connection of the PCB interposer 18 a to thewireless transmitter/receiver in the SoC 12 is made by wire bonding 22to pads 38. The use of PCB is important because the flexible substrate36 a has a higher signal loss and its thin metal trace usually resultsin high resistivity, not suitable for relaying high frequency and weakelectrical signal.

In a preferred embodiment, the all or a portion of the stimulationimplant 10 a is encapsulated in a capsule 26 comprising a biocompatiblematerial (i.e. silicone, PDMS, glass, titanium, ceramic, and epoxy),which may be similar to the shape to a medicine capsule.

FIG. 2 illustrates an alternative configuration of a GI implant 10 bhaving the battery, passive and active components (collectively 14 b)integrated with or adjacent to the SoC 12 on the same side or bottomside of the flexible substrate 36 b. In this configuration, theresistance of the metal traces on the flexible substrate 36 b are takeninto consideration.

A PCB antenna 18 b is disposed for wireless signal transmission andrecording. Substrate 36 b comprising an electrode array 16 b is providedfor delivering GI stimulation. In a preferred embodiment, the substrate36 b comprises a flexible material, such as polyimide, parylene,silicone, or PDMS, or the like, with a thickness generally ranging from5 um to 50 um. The flexible substrate 36 b also serves as a softinterposer board in which electrical connections are made by depositionof metal bumps 28 (e.g., Pt, Pt black, Titanium, gold, etc.) at pads 34.An SoC 12 is positioned on a bottom surface of the flexible substrate 36b such that specified openings (e.g., round shape or square shapeopenings) disposed through the flexible substrate 36 b expose the metalpads 32 of the SoC 12 to the metallic bumps 28 or other passive/activecomponents 14 b. The openings on the substrate 36 b are aligned to themetal pads 32 of the SoC enable its operation. In one embodiment,Gold/alumina bumps 28 with a diameter from 20-50 μm are positioned ontop of the opening to link the SoC 12 and the flexible substrate 36 b.

The SoC 12 sits on top of a PCB antenna 18 b, which has patterned metalto serve as an antenna and for the connection with the battery incomponents package 14 b. The connection of the PCB antenna 18 b to theSoC 12 is made by wire bonding 22 to pad 38.

In a preferred embodiment, the all or a portion of the stimulationimplant 10 b is encapsulated in a capsule 26 comprising a biocompatiblematerial (e.g., silicone, PDMS, glass, ceramic, titanium, epoxy, or likematerial), which may be similar to the shape to a medicine capsule.

The GI/nerve implant 10 b also comprises one or more implant coils/wireantenna 40. The implantable coils 40 are preferably configured to couplean external device or controller (not shown) via a wireless inductivecoupling such that one or more of power and commands may be transmittedto/from the external device to apply a stimulus voltage at a treatmentlocation in a body tissue. In one embodiment (not shown), the inductivecoupling is achieved through a power and stimulator module and reversetelemetry module connected to the implant coil. Wherein the implant coilis inductively coupled to an external power coil that is configured tosend a power signal to said implant coil, as well as send controlstimulation parameters and process reverse telemetry.

As shown in FIG. 2, the flexible substrate 36 b is folded over (in aU-shape to wrap around below the SoC 12 and components 14 b, and has anembedded array of electrodes 16 b directed downward from the device.

Referring now to FIG. 3, an alternative configuration of a GI implant 10c is illustrated that is similar to the embodiment of FIG. 2 except thatthe flexible substrate 36 c upon which the electrode array 16 c isdisposed is laid straight depending on the needs of different clinicalapplications.

For critical connections, such as power, ground connection and highfrequency signal input/output, bonding wires 22 are used to form theelectrical connection, in addition to using the metal trace on theflexible substrate 36 c, for the purpose of minimizing the parasiticresistance/capacitance contributed by the flexible substrate 36 c.

In a preferred embodiment, the substrate 36 c comprises a flexiblematerial, such as polyimide, parylene, silicone, or PDMS, or the like,with a thickness generally ranging from 5 um to 50 um. The flexiblesubstrate 36 c also serves as a soft interposer board in whichelectrical connections are made by deposition of metal bumps 28 (e.g.,Pt, Pt black, Titanium, gold, etc.) at pads 34. An SoC 12 is positionedon a bottom surface of the flexible substrate 36 c such that specifiedopenings (e.g., round shape or square shape openings) disposed throughthe flexible substrate 36 c expose the metal pads 32 of the SoC 12and/or other passive/active components 14 c (which may also comprise abattery and/or antenna) to the metallic bumps 28. The openings on thesubstrate 36 c are aligned to the metal pads 32 of the SoC 12 andcomponents 14 c to enable their operation. In one embodiment,Gold/alumina bumps 28 with a diameter from 20-50 μm are positioned ontop of the openings to link the SoC 12 and components 14 c and theflexible substrate 36 c.

One or more of the SoC and active/passive components compriseapplication programming and a processor for activating the electrodearray 16 according to a stimulation waveform as shown in FIG. 5 or 6,discussed in more detail below.

FIG. 4A through FIG. 4C show the bottom views of the intraluminalelectrode arrays (50 a through 50 c, respectively). So that thegastrointestinal tract is not obstructed, electrode arrays 50 a through50 c preferably have footprints such that length (L1) and width (W1) andheight (into page) are configured to be less than about 1 cm. Suturesholes 52 may be provided through the substrate, and in one configurationthe suture holes 52 are distributed on four sides of the electrode array50 a, 50 b, and 50 c to allow clinicians purchase for anchoring thedevice inside the GI tract or the nerve through a buckle (not shown).For the application of transient GI implant for POI, the size of thesuture holes 52 is generally in the range of 0.05 to 0.7 mm, allowingthe use of synthetic absorbable/biodegradable suture wires (not shown)with different gauges. The absorbable/biodegradable suture wires areconfigured to dissolve after a period of time, thus allowing the implantto pass out of the GI tract without surgery for removal.

The number of electrodes 16 may vary from the simplest configuration oftwo electrodes in the array 50 a of FIG. 4A to the four-electrode array50 b of FIG. 4B, six-electrode array 50 c of FIG. 4C, as well as anynumber of electrodes, or even a cuff electrode for nerve stimulation andrecording. In the two-electrode configuration 50 a of FIG. 4A, oneelectrode serves as the stimulation/recording electrode and the otherone is the return/ground electrode or vice versa.

In a preferred embodiment, each of the electrodes in the array 50 athrough 50 c are individually addressable for stimulation at distincttiming, frequency, or power.

The size of the electrodes 16 preferably ranges to be below 9 mm² (e.g.,3 mm×3 mm) with a spacing of <2 mm. In the electrode arrayconfiguration, the size of each electrode is set to <2 mm² with aspacing of <2 mm. Each electrode 16 can be configured as ground/return,stimulation, recording, or concurrent stimulation and recordingelectrode. Multiple electrodes 16 can be used to deliver stimulussimultaneously with different parameters. The material of the electrode16 can be silver, gold, platinum, titanium, or alloys. The electrodeshape can also be strip, instead of round shape as shown, to ensure thedevice can interface with the biological tissue, regardless of itsdisplacement. In one embodiment, pH sensing material may be coated onthe electrode 16 for pH measurement.

FIG. 5 shows one configuration of the current stimulation waveforms thatmay be delivered from any of the electrodes 16 or electrode arrays inthe intraluminal implants detailed above. It is appreciated that while asingle polarity stimulus is shown in FIG. 5 for the purpose ofillustration, the stimulus may also be a biphasic stimulus (i.e. eithercathodic first and anodic first), or other form know to one of skill inthe art. Stimulus A is a high intensity pulse used to trigger themuscle/neurons. Its pulse width, PW1, is configured to be in the rangeof 0.5 ms-100 ms, with intensity from 0.5 mA to 10 mA. The stimulationfrequency, 1/T₁, is preferably set from 0.01 Hz to 300 Hz. A lowintensity short stimulus, B₁, is inserted between each strong stimulus.Stimulus B₁ should be issued after the electrode overpotential is backto its baseline value after the perturbation of stimulus A. Theseparation between stimuli A and B₁ (i.e., T₂) can be more preciselydetermined based on the electrode-tissue impedance.

In one embodiment, the purpose of stimulus B₁ is to monitor the tissueimpedance during the contraction and/or relaxation of the GI smoothmuscle. Tissue impedance is derived by measuring the electrodeoverpotential evoked by stimulus B₁. The pulse width of stimulus B₁ canbe set in the range of 10 μs to 1000 μs, based on the size of theelectrode 16 (i.e., impedance of the electrode used) such that thedelivered current (i.e., electric charge) flows to the tissue throughthe non-faradic reaction via the double layer capacitance of theelectrode-tissue interface. Under such, the varying tissue impedance canbe simply acquired by measuring the peak evoked electrode overpotentialresulting from stimulus B and the known stimulation intensity. Theintensity should be set to a range in order to ensure that the evokedelectrode overpotential does not saturate the signal-recording circuitof the implant. Stimulation intensity used in our proof-of-conceptexperiment is from <1 μA to 1 mA.

In order to measure the GI propagation wave during smooth musclecontraction and/or relaxation, multiple electrodes can be used for GIimpedance/motility recording. This is done by employing other electrodesto deliver low-intensity stimuli (e.g., B₂ and B₃) and carefullyassigned a firing timing offset (i.e., T₂-T₄≠0). If B₁₋₃ have differentpolarity than the stimulus A, firing timing of B₁₋₃ needs to be offsetfrom that of stimulus A to ensure that the current contributed by B₁₋₃does not flow directly to the electrode that delivers stimulus A,affecting the accuracy of the impedance/motility measurement.

Because stimuli B₁-B₃ are not designed to fire simultaneously, specialconsideration must be taken to determine the minimum delays between eachstimulus. This is important, as many stimulators adopt passive charge toremove its residual charge by shorting the electrodes to theground/reference electrode after each stimulation. It is thereforepossible that during the firing of B₁ the injected current would simplyflow to the adjacent electrode configured to fire B₂, if it happens toperform passive discharge. The firing delay of stimuli forimpedance/motility measurement (e.g., T₂, and T₃) can be determinedbased on the discharging time estimated by deriving the impedance ofelectrode-tissue interface. At least, T₁-T₃ should be set at least 2times the value of PW₂.

In another embodiment, the delivered stimuli are configured to mimic thenature electrophysiological signals, including one or more of: EMG, EGG,ECG, action potentials, and local-field potentials.

FIG. 6 shows another configuration of stimulation parameters. Severalpulses are grouped to trigger the activation of muscle/neurons duringthe duration of T₄. T₄ is generally set to the range between 0.5 ms to60 s, depending on the number of stimulus to be sent. The stimulationfrequency, 1/T₅, generally ranges from 0.01 Hz to 300 Hz. Between eachgroup of stimuli, again, low intensity stimulus is inserted forimpedance/motility measurement, in which the firing frequency, 1/T₆,will ideally be the same as 1/T₅ to avoid the overlapping of both typesof stimuli. The stimulus for impedance measurement can be either asingle pulse, a pulse train, a sinusoidal wave, or the like.

B. Non-Invasive Gastrointestinal Stimulator

In addition to performing intraluminal stimulation and motilityrecording via the implant 10 a through 10 c shown in FIG. 1 through FIG.3, non-invasive transcutaneous electrical stimulation may also beemployed for gastrointestinal therapeutics.

FIG. 7A shows a front view of ventral body anatomy with acupuncturepoints and the transcutaneous electrical stimulation array 60 of thepresent description. FIG. 7B shows a side view of the patient with atranscutaneous GI stimulation system 100 and transcutaneous electricalstimulation array 60 disposed on the abdomen/abdominal wall of a patientin accordance with the present description. Unlike other conventionaltranscutaneous electrical nerve stimulation (TENS) devices that usespairs of electrodes to perform bipolar stimulation for pain suppressionand simple stimulation strategy/waveform, a multiple electrode array 60is implemented to allow: 1) the spatial steering of the injectedelectrical charge to the target locations/tissues of interest within theanatomy; 2) a unique retarded stimulation waveform to minimize theunwanted edge effect during stimulation; and 3) electrode structuresthat not only lower the electrode-tissue interface impedance, but alsoavoid the influence of sweat that might create direct short circuitbetween two adjacent electrodes.

Referring to FIG. 7A, the diameter (D₁) of the electrodes 16 generallyranges from 5 mm to 50 mm. The spacing (D₂) between electrodes generallyranges from 3 mm to 100 mm. The number of electrodes (M by N) may bevaried based on the area of the stimulation target region. The electrodearray 60 may be directly placed on top of the acupuncture points 62 thatgovern/facilitate the functionalities of the internal organs (i.e.,stomach, intestine, colon, bowel, liver and so on). Each electrode 16 inelectrode array 60 is independently addressable for stimulation, andmultiple electrodes 16 may be used to deliver stimuli simultaneouslywith different parameters to shape the resulting electrical field (FIG.7B) for focused stimulation. Each electrode can also be used to recordthe electrophysiological signals produced by the GI tractnon-invasively.

Thus, stimulation system 100 is not only capable of stimulating theacupuncture points 62, but the stimulation current can be steered andapplied to the target inside the body. In one example, if the patientreceived a surgery and has a surgical cut 64 made on his colon,stimulation current can be delivered from the electrodes on theabdominal wall which is close to the colonic segment undergoing surgery.By deliberately setting the stimulation parameters, the current thatwould otherwise spread to unwanted (i.e. non-treatment) regions withinthe body is minimized. In the example shown in FIG. 7A, a cathodic firstbiphasic stimulus is applied to a center electrode 67, and four adjacentelectrodes 65 are given anodic first stimuli concurrent to focalize thestimulation current. More complex current weighting can be applied basedon the depth, size, and location of the stimulation site. The durationfor continuous stimulation should generally be less than 30 minutes inorder to avoid unwanted tissue/neural damage. In another example, theelectrode array can be placed on the back of the patient to stimulatethe spinal ganglion for the modulating of GI motility and autonomicnervous system.

Referring to FIG. 7B, a return/ground electrode 66 is positioned on theback of the subject opposite the stimulation array 60, or vice versa. Inone application, the location of return/ground electrode 66 may be closeto the midline or midline of the thoracic, lumbar, and sacral spines,allowing the stimulation current to pass through spinal ganglions whereneuron/sympathetic/parasympathetic nerves reside, and then to becollected by the return/ground electrode 66.

With respect to a patient's skin, the stratum corneum (SC) is theoutmost part of the skin, with a thickness in the range of 10-40 μm, andis thought to be the main contributor of the skin impedance.Conventional planar electrodes used for stimulation inject current fromthe high impedance SC layer, and thus inevitably set a requirement ofhigh compliance voltage for the stimulator. For an electrode-tissueimpedance of 2 kΩ using a planar electrode, delivering a 100 mA stimulusnecessitates a high compliance voltage of 200 V for the stimulator,drastically increasing the its power consumption and possibly resultingin skin burning. Equally important, sweating is a non-negligible concernthat needs to be taken into consideration during stimulation. Theaverage density of sweat gland is 200 per square centimeter. The sweatgland resides in the dermis layer, and its duct conveys sweat to thesurface of the skin. Excessive sweating may create direct shortingbetween electrodes or cause the stimulation current to spread toundesired targets.

FIG. 8 is an enlarged side view of the electrode array 60 structure inaccordance with the present description. In a preferred embodiment, theelectrode array 60 comprises a plurality of conical penetrating spikeelectrodes 16 array, with only the tips 54 of the spikes exposed. Thesubstrate 56 supporting the electrodes 16, and a lower portion of thespike are preferably electrically insulated, e.g., by coating a lowerportion of the spike and substrate 56 with a layer of non-conductivebiocompatible material (i.e., epoxy, PDMS, polyimide, parylene, andsilicone). The insulation layer ensures excessive sweat will not createshorting between electrodes, especially in the scenario that a highintensity current is used for neuromodulation. The height of theelectrode 16 is configured to be larger than the thickness of the SClayer (e.g., 15-140 μm), and pierce the skin to bypass thehigh-impedance SC layer and the sweat gland. With such configuration,the compliance voltage of the stimulator may be much less stringent. Inone example, the height hi of the exposed tip 54 of each spike on oneelectrode ranges from 5 μm -100 μm with an angle of a, where α rangesfrom 5° to 45°. The height of the insulated section (h₂) of each spikemay be set according to desired protection from electrode 16 shorting.Since the electrode tips 54 are exposed to low-impedance skin layers,under the same intensity of stimulus as conventional planar electrode orspike electrode with no insulation layer, less power is consumed (i.e.,Power=Current×Impedance²), and hence less heat is generated forminimizing the possibility of skin burning.

The shape of the electrode substrate 56 is also configured formitigating the stimulation edge effect, in which the edge of theelectrode 16 has the strongest electric field during the onset ofelectrical stimulation. Edge effect results in uncontrolled strongE-field that possibly damages the tissue/neuron/skin. Thus, unlikewidely used circular/square/rectangular electrodes, the electrodesubstrate 56 presented herein is configured in such a way that its shapeis symmetric, but has different path lengths from the center to the edgeof the electrode for reducing the edge effect, such as a heptagram andoctagram. The array 60 may further comprise an insulated electron holder58 and conductor 68 that provides transfer of electrical current to theelectrons. As shown in the embodiment of FIG. 8, the shown series of sixspikes make up one electrode 16.

FIG. 9A and FIG. 9B show images of exemplary stimulation waveforms thatmay be used for stimulating a target region of interest. FIG. 9A shows aretarded stimulation waveform that has been commonly used to reduce theedge effect. In contrast to the square stimulation pulse, apre-determined rising time of the stimulus (Δt) is inserted forinjecting a stimulus with the intensity I_(peak). Though this is amethod for mitigating edge effect, it imposes stringent hardwarespecification for the stimulator when high frequency stimulus isrequired. For example, there are applications that fire 5-10 kHzstimulus (0.1 ms pulse width) in the form of pulse train into thetissue. The purpose of the 5-10 kHz stimulus is reported to block thepain fiber so that the subject does not feel pain during thestimulation. If the retarded waveform has a rising time of 1/10 th ofits pulse width and there are 10 steps increment for the current to gofrom 0 to I_(peak), the circuits of the stimulator, such as DAC, need tobe able to produce its output rate at a minimum of 1 Mbps, possiblyincreasing the design complexity and performance requirement of thecircuit components.

FIG. 9B illustrates a stepwise stimulation waveform using a stepwisepulse train to mitigate the stimulation edge effect in accordance withthe present description. Each pulse is either mono-phasic or biphasicstimulus. I_(peak) is the targeted stimulation intensity, which may varyfrom sub-1 mA to 300 mA. PW₃ and PW₄ are the pulse widths of eachstimulus, which do not need to be equal, (as well as all other pulses inpulse train). In one embodiment, the pulse width varies from 10 μs to 10ms. T_(gap) is the separation between two consecutive pulses and mayvary from 0 to 100 times the pulse width. Again, T_(gap) can varybetween each consecutive two pulses. Lastly, T_(period) is theseparation between two pulse trains and 1/T_(period), is configured tobe from sub-1 Hz to 300 Hz. The stimulation waveform is generated byfirst determining the number of steps N and the peak stimulation currentI_(peak). For example, if N=10 and I_(peak) is 100 mA, 9 (i.e. N-1)step-up current pulses would first be generated before reaching 100 mA.Subsequently, based on the user's specification and clinical performanceof the subject, a specific number of stimuli with 100 mA intensity arefired. In the end of the pulse train stimulation, corresponding 9step-down pulses are fired in the reciprocal order of the initial 9step-up current pulses. When multiple channels are turned onsimultaneously, the onset time of each group of pulse train isinterleaved to avoid the concurrent firing, meaning T_(delay) should belarger than the length of the pulse train and smaller than T_(period).This arrangement alleviates the design burden of the power managementcircuits in the stimulator, and avoids the risk of injecting a largecurrent into the subject. In the scenario of DC current stimulation,concurrent firing of multi-channel would limit the overall injectedcurrent to <10 mA to avoid tissue/neuron damage.

FIG. 10A through FIG. 10D show various stimulation current injectionschemes in accordance with the present description. In addition tostimulating through a specific electrode or a group of electrodesconcurrently with different current ratios, the stimuli may be deliveredinto the electrodes of interests based on an order defined by theclinician/researcher/scientist/patient. The purpose of the orderedstimulation onset is to mimic to physical massage in which muscles arekneaded in a certain order. A subset of examples of the stimulationorder is demonstrated in FIG. 10A through FIG. 10D, which show an 8×8electrode array 60 (for exemplary purposes only). The arrow signindicates the direction of onset sequence of the stimulation.

FIG. 10A shows stimulated electrodes 70 a in an onset sequence ofstimulation horizontally from left to the right. Electrodes 72 a are notengaged in this sequence.

FIG. 10B shows stimulated electrodes 70 b in a diagonal onset sequenceof stimulation. Electrodes 72 b are not engaged in this sequence.

FIG. 10C shows stimulated electrodes 70 c in a clockwise rectangularonset sequence of stimulation. Electrodes 72 c are not engaged in thissequence. FIG. 10D shows stimulated electrodes 70 d in a clockwisespiral onset sequence of stimulation. Electrodes 72 d are not engaged inthis sequence.

Multiple electrodes can also be activated to deliver electrical stimulito through the skin.

It is appreciated the sequences shown in FIG. 10A through FIG. 10D arefor illustrative purposes only, and any arrangement or number ofsequences may be implemented according to the desired therapy and/ortarget tissue region.

FIG. 11 shows a schematic block diagram of the non-invasivetranscutaneous stimulator system 100 of the present description. Thesystem 100 is configured for use with a mobile device 104 (i.e., cellphone, smart watch, tablet, laptop or like device) to transmit commands122 to the stimulator through a wireless signal such as Bluetooth orWiFi. The command 122 is received by a wireless circuitry 110 andsubsequently processed by a microprocessor 102 (e.g., MCU/FPGA/DSP or acustomized application specific integrated chip (ASIC)), and then storedin the memory 106. Based on the received commands, the applicationprogramming 108 stored in memory 106 executes instructions related tocommand 122 via MCU/FPGA/DSP/ASIC 102, which delivers the controlsignals to the digital-to-analog converters (DACs) 114 to configure thestimulation current. Mobile device 104 may also comprise applicationprogramming (in addition to or in place of instructions in programming108) that contains instructions for providing the command 122stimulus/stimuli, and associated memory for storing the programming andprocessor for executing and transmitting command 122.

It is important to point out that conventional stimulator designs adoptcurrent mirrors to amplify the output current of the DAC and to conveythe amplified current to the stimulator output stage. If thisconfiguration is implemented using integrated microelectronics, the DACusually outputs a small current while the current mirror is designatedto support high current gain to optimize the power consumption of theelectronics at the cost of larger chip area. In contrast, if thestimulator is to be developed using off-the-shelf components, there aregenerally no off-the-shelf high-gain current mirrors available, and thusinevitably increases the footprint of the stimulator when a high gainration is desired. Moreover, as a high-compliance voltage is requiredfor the stimulator to accommodate various electrode-tissue impedancesand large stimulation current, the adoption of current mirrors furtherincreases the power consumption of the stimulator.

Hence, a viable solution is setting the stimulation current by directlyconfiguring the base/gate voltage of the transistor (e.g., BJT orMOSFET). In the stimulator of FIG. 11, BJT₁ and BJT₂ form the outputstage of the stimulator. R₃ and R₄, along with the current generated bythe PGA outputs, form the base current of the BJTs or the overdrivevoltage when MOSFETs are used. V+ and V− are the supply voltage of thestimulator and their value ranges from ±10V to ±100V to support a widerange of stimulation current and various types of electrodes. The basenode of the BJT₁₋₂ is tied to its emitter through the pull-up resistor,R₃₋₄, to ensure there is no output current when the stimulator is set tobe off and no command signal is issued. Subsequently, when stimulationis on, the DAC's 114 deliver current or voltage output to theprogrammable gain amplifiers (PGAs) 116. The (PGAs) 116 can be avoltage- or current-mode amplifier that generate voltage or currentoutputs. Note that the function of resistor R₁ is to convert the outputcurrent of the DACs 114 into voltage if a current-mode DAC is adopted.The DACs 114 can also be integrated in the ASIC so that multiple DACscan be incorporated to build a multi-channel stimulator without takingtoo much space of the stimulator. The gain of the PGA 116 is set basedon the desired output current. The PGA 116 then drives the BJT through ahigh pass filter (HPF) made of R₃₋₄ and C₁₋₂. The use of the HPFprovides the advantage that the DAC/PGA can be powered using low supplyvoltages (e.g., 1.8V/3.3V/5V) to significantly reduce the overall systempower consumption. During the stimulation, the stimulation command issent preferably using the pulse waveform, e.g., similar to the waveformof FIG. 9B, to the base of the BJT (or the gate of a MOSFET). Theamplitude and width of each pulse then results in the intendedstimulation current waveform set by the user.

A discharge switch, S1 118, is connected to the stimulator output.Switch 118 is shorted to ground/return electrode 66 at the end of eachstimulus to remove the residual charge. The control voltage to thedischarge may be set to avoid the undesired turn-on of the dischargeswitch 118 during stimulation. For example, the control voltage can beeither V+ to enable the charge cancellation or V− to disable chargecancellation. A one-to-N output de-multiplexer 120 is also connected tothe stimulator output for the purpose of expanding the number ofelectrodes in array 60 driven by the stimulator.

An impedance measurement circuit 112 is also connected to the stimulatoroutput to measure the electrode-tissue impedance. This measurement canbe performed, for example, by injecting a sinusoidal/square current andmeasuring the evoked electrode bio-potential, or by using the techniquesdescribed in PCT International Publication No. WO 2015/168162 publishedon Nov. 5, 2015 and incorporated herein by reference in its entirety.Measuring impedance can ensure the reliability of the electrode and beused as indicator to dynamically adjust the compliance voltage of thestimulator for power saving. For instance, if the electrode-tissueimpedance is 0.5 kohm and a 100 mA stimulus is delivered to theelectrode, then the compliance voltage should be set as ±50V. If thestimulation intensity is dropped to 50 mA, the required compliancevoltage is only ±25V. Adaptively adjusting the compliance voltage basedon the known stimulation intensity and the electrode-tissue impedancecan optimize the power efficiency of the stimulator.

The impedance measuring circuit may also measure conductivity betweenany two electrodes to determine if a short circuit has formed betweenelectrodes and monitor a reparation rate of the patient.

FIG. 12 shows a schematic diagram of a power management circuit 150 tobe used with stimulation system 100. Its main function is to generateboth high negative and positive supply voltages for the stimulator froma battery 154. The first DC-DC power converter 156 produces 1.8/3.3/5Vfrom the battery 154, and the 2^(nd) DC-DC power converter 158produces−1.8/−3.3/−5V by taking the 1.8/3.3/5V input. The 3^(rd) DC-DCpower converter 160 subsequently generates both positive and negativehigh compliance voltages. Capacitors, C₃ and C₄, are connected to thepower converter outputs and share the same common node connected to theground/return electrode 60/66. The use of C₃₋₄ helps define the positiveand negative compliance voltages 162 a/162 b relative to the bodypotential sensed by the ground/return electrode 60/66. Once theelectrode-tissue impedance 164 is known and the stimulation intensity isdetermined, the MCU/FPGA/DSP/ASIC 102 sends a command to the voltagetuning circuits 152, which may comprise a resistor ladder, to adjust theoutput of the 3^(rd) DC-DC power converter 160.

Embodiments of the present technology may be described herein withreference to flowchart illustrations of methods and systems according toembodiments of the technology, and/or procedures, algorithms, steps,operations, formulae, or other computational depictions, which may alsobe implemented as computer program products. In this regard, each blockor step of a flowchart, and combinations of blocks (and/or steps) in aflowchart, as well as any procedure, algorithm, step, operation,formula, or computational depiction can be implemented by various means,such as hardware, firmware, and/or software including one or morecomputer program instructions embodied in computer-readable programcode. As will be appreciated, any such computer program instructions maybe executed by one or more computer processors, including withoutlimitation a general-purpose computer or special purpose computer, orother programmable processing apparatus to produce a machine, such thatthe computer program instructions which execute on the computerprocessor(s) or other programmable processing apparatus create means forimplementing the function(s) specified.

Accordingly, blocks of the flowcharts, and procedures, algorithms,steps, operations, formulae, or computational depictions describedherein support combinations of means for performing the specifiedfunction(s), combinations of steps for performing the specifiedfunction(s), and computer program instructions, such as embodied incomputer-readable program code logic means, for performing the specifiedfunction(s). It will also be understood that each block of the flowchartillustrations, as well as any procedures, algorithms, steps, operations,formulae, or computational depictions and combinations thereof describedherein, can be implemented by special purpose hardware-based computersystems which perform the specified function(s) or step(s), orcombinations of special purpose hardware and computer-readable programcode.

Furthermore, these computer program instructions, such as embodied incomputer-readable program code, may also be stored in one or morecomputer-readable memory or memory devices that can direct a computerprocessor or other programmable processing apparatus to function in aparticular manner, such that the instructions stored in thecomputer-readable memory or memory devices produce an article ofmanufacture including instruction means which implement the functionspecified in the block(s) of the flowchart(s). The computer programinstructions may also be executed by a computer processor or otherprogrammable processing apparatus to cause a series of operational stepsto be performed on the computer processor or other programmableprocessing apparatus to produce a computer-implemented process such thatthe instructions which execute on the computer processor or otherprogrammable processing apparatus provide steps for implementing thefunctions specified in the block(s) of the flowchart(s), procedure (s)algorithm(s), step(s), operation(s), formula(e), or computationaldepiction(s).

It will further be appreciated that the terms “programming” or “programexecutable” as used herein refer to one or more instructions that can beexecuted by one or more computer processors to perform one or morefunctions as described herein. The instructions can be embodied insoftware, in firmware, or in a combination of software and firmware. Theinstructions can be stored local to the device in non-transitory media,or can be stored remotely such as on a server, or all or a portion ofthe instructions can be stored locally and remotely. Instructions storedremotely can be downloaded (pushed) to the device by user initiation, orautomatically based on one or more factors.

It will further be appreciated that as used herein, that the termsprocessor, hardware processor, computer processor, central processingunit (CPU), and computer are used synonymously to denote a devicecapable of executing the instructions and communicating withinput/output interfaces and/or peripheral devices, and that the termsprocessor, hardware processor, computer processor, CPU, and computer areintended to encompass single or multiple devices, single core andmulticore devices, and variations thereof.

From the description herein, it will be appreciated that the presentdisclosure encompasses multiple embodiments which include, but are notlimited to, the following:

1. An implantable apparatus for stimulating a target anatomy,comprising: a flexible substrate configured to house a plurality ofelectrodes disposed in an electrode array; a system-on-chip (SoC)coupled to the flexible substrate; wherein the SoC is positioned on oneside of the flexible substrate such that specified openings disposedthrough the flexible substrate align with conductive pads of the SoC;and passive/active components coupled to the SoC; wherein theimplantable apparatus is configured to be installed at a treatmentlocation of a gastrointestinal (GI) tract of a patient or the vagusnerve and its associated branches; and wherein the electrode array isconfigured to be activated to electrically modulate and record one ormore of GI tract smooth muscles, associated neurons, and nerve fibers torestore GI motility and inflammatory responses within the GI tract.

2. The system, apparatus or method of any preceding or followingembodiment, further comprising: a printed circuit board (PCB) antennacoupled to the SoC, the PCB antenna configured to receive signals froman external device for wireless activation of the electrode array andrecording of signals from the electrode array; wherein the SoC isdisposed between the PCB antenna and the flexible substrate.

3. The system, apparatus or method of any preceding or followingembodiment, wherein the PCB antenna acts as an interposer between theSoC and a battery configured to power the apparatus.

4. The system, apparatus or method of any preceding or followingembodiment, wherein the flexible substrate wraps around the SoC and PCBantenna.

5. The system, apparatus or method of any preceding or followingembodiment, wherein all or a portion of the apparatus is encapsulated ina biocompatible material.

6. The system, apparatus or method of any preceding or followingembodiment, wherein the flexible substrate comprises a plurality ofsuture holes for anchoring the apparatus within the GI tract via anabsorbable suture.

7. The system, apparatus or method of any preceding or followingembodiment, wherein one or more of the SoC and active/passive componentscomprise: a processor; a non-transitory memory storing instructionsexecutable by the processor; wherein said instructions, when executed bythe processor, perform steps comprising: activating the electrode arrayaccording to a user-determined stimulation waveform that is configurablebased on the patient's physiological status.

8. The system, apparatus or method of any preceding or followingembodiment, wherein the stimulation pattern comprises: a periodicstimulus comprising high-intensity pulses used to trigger muscle orneurons in the GI tract; a low-intensity stimulus comprising a shortpulse inserted between each high-intensity stimulus; and wherein thelow-intensity stimulus is used to monitor the tissue impedance during acontraction or relaxation of the GI smooth muscle.

9. The system, apparatus or method of any preceding or followingembodiment, wherein the tissue impedance is derived by measuring theelectrode overpotential evoked by the low-intensity stimulus.

10. The system, apparatus or method of any preceding or followingembodiment, wherein said instructions, when executed by the processor,further perform steps comprising: delivering a second low-intensitystimulus via a second electrode in the electrode array separate from afirst electrode in the electrode array, the first electrode generatingthe first low-intensity stimulus; and measuring a GI propagation waveduring the smooth muscle contraction/relaxation.

11. The system, apparatus or method of any preceding or followingembodiment, wherein the low-intensity stimulus pulse is inserted betweena group of at least two high-intensity stimulus pulses.

12. A method for treating post-operative ileus, comprising: installingthe disposable implant at a treatment location of a gastrointestinal(GI) tract of a patient; and electrically modulating one or moregastrointestinal tract smooth muscles and associated neurons to restoreGI motility and reduce inflammatory responses.

13. The system, apparatus or method of any preceding or followingembodiment, further comprising: wirelessly recording the GI motility bymeasuring one or more of the electrode-tissue impedance, GI pH value,and transit time.

14. The system, apparatus or method of any preceding or followingembodiment, further comprising: applying an electrical stimulation atthe treatment location at or near a vagus nerve ending to reduce a levelof tumor necrosis factor (TNF) associate with the GI tract.

15. The system, apparatus or method of any preceding or followingembodiment, wherein modulating is performed by activating the electrodearray according to a user defined stimulation pulse waveform that isfurther adjustable based on the patient's physiological feedback tooptimize treatment efficacy.

16. The system, apparatus or method of any preceding or followingembodiment, wherein the stimulation pulse waveform is generated via oneof more commands sent wirelessly to the implant from a device externalto the patient.

17. The system, apparatus or method of any preceding or followingembodiment, wherein the stimulation waveform is configured forsimultaneous GI stimulation and motility recording, and comprises: aperiodic stimulus comprising high-intensity pulses used to triggermuscle or neurons in the GI tract; a low-intensity stimulus comprising ashort pulse inserted between each high-intensity stimulus; and whereinthe low-intensity stimulus is used to monitor the tissue impedanceduring a contraction or relaxation of the GI smooth muscle.

18. The system, apparatus or method of any preceding or followingembodiment, wherein the tissue impedance is derived by measuring theelectrode overpotential evoked by the low-intensity stimulus.

19. The system, apparatus or method of any preceding or followingembodiment, the method further comprising; delivering a secondlow-intensity stimulus via a second electrode in the electrode arrayseparate from a first electrode in the electrode array, the firstelectrode generating the first low-intensity stimulus; and measuring aGI propagation wave during the smooth muscle contraction/relaxation.

20. The system, apparatus or method of any preceding or followingembodiment, wherein the low-intensity stimulus pulse is inserted betweena group of high intensity stimulus pulses.

21. A system for stimulating a target tissue of a patient,comprising:(a) a stimulator comprising an array of electrodes configuredto transcutaneously deliver an electric field into the target tissuefrom a first surface on the patient, each electrode the array beingindependently addressable for stimulation at distinct timing orfrequency; (b) a return electrode configured to be positioned on asecond surface of the patient opposite the target tissue from the firstsurface; (c) a processor; (d) a non-transitory memory storinginstructions executable by the processor; (e) wherein said instructions,when executed by the processor, perform steps comprising: (i) deliveringstimuli to the array of electrodes such that the array simultaneouslywith different stimulation parameters; and (ii) emitting a shaped andfocused electrical field from the array into the target tissue forstimulation of the target tissue; (iii) wherein at least two of theelectrodes in the array are sequentially activated with a specifiedtiming so as to generate the shaped and focused electrical field.

22. The system, apparatus or method of any preceding or followingembodiment, wherein said delivering stimuli to the array comprises:applying a cathodic biphasic stimulus to a center electrode; andapplying an anodic biphasic stimulus to four electrodes adjacent to thecenter electrode.

23. The system, apparatus or method of any preceding or followingembodiment, further comprising: a mobile device wirelessly coupled tothe stimulator; wherein the command is delivered to the stimulator fromthe mobile device; and wherein a recorded physiological signal isdelivered to the mobile device from the stimulator.

24. The system, apparatus or method of any preceding or followingembodiment: wherein the stimulator is configured to be positioned on anabdominal wall or back surface of the patient; and wherein the returnelectrode is configured to be positioned on a surface opposite theabdomen of the patient from the stimulator such that the shaped andfocused electrical field is directed through the abdomen to be collectedby the return electrode.

25. The system, apparatus or method of any preceding or followingembodiment, wherein the shaped and focused electrical field is directedthrough spinal ganglions where neurons, sympathetic, or parasympatheticnerves.

26. The system, apparatus or method of any preceding or followingembodiment, wherein the stimuli are delivered as a stepwise stimulationwaveform comprising a plurality of spaced apart stepwise pulse trainsconfigured to mitigate the stimulation edge effect.

27. The system, apparatus or method of any preceding or followingembodiment, wherein each stepwise pulse train comprises: a series ofstep-up stimulation pulses each having a current that incrementallyincreases until a specified peak stimulation current is achieved; one ormore subsequent peak intensity pulses at the peak stimulation current;and a series of step-down stimulation pulses each having a current thatincrementally decreases.

28. The system, apparatus or method of any preceding or followingembodiment, wherein the number of step-up stimulation pulses matches thenumber of step-down stimulation pulses.

29. The system, apparatus or method of any preceding or followingembodiment: wherein two or more electrodes are activated simultaneously;and wherein the onset time of the stepwise pulse train delivered to eachelectrode is interleaved to avoid the concurrent firing of stepwisepulse trains in separate electrodes to ensure the overall stimulationcurrent does not exceed a safe stimulation limit.

30. The system, apparatus or method of any preceding or followingembodiment, wherein the electrode array comprises: a plurality ofconical spikes each having an electrically insulated portion and anon-insulated tip; wherein the non-insulated tip has a shape and heightconfigured to penetrate the patient's skin to bypass one or more of orsweat gland of the patient's skin.

31. The system, apparatus or method of any preceding or followingembodiment, wherein stimulator comprises: a processor; one or moredigital-to-analog converters (DACs) coupled to the processor; and anoutput stage comprising one or more transistors; wherein the stimulationcurrent of the stimuli delivered to the electrodes is directlyconfigured as a function of base/gate voltage of the one or moretransistors.

32. The system, apparatus or method of any preceding or followingembodiment, further comprising: one or more programmable gain amplifiers(PGAs) coupled to the one or more DACs; and a high pass filter coupledto the output stage; wherein the current or voltage output are deliveredbetween the one or more DACs and the one or more PGAs to drive the oneor more transistors of the output stage through the high pass filter(HPF).

33. The system, apparatus or method of any preceding or followingembodiment, further comprising: a discharge switch coupled to an outputof the stimulator and the return electrode; wherein discharge switch isshorted to return electrode at an end of each stimulus or group ofstimuli to remove any residual charge when necessary.

34. The system, apparatus or method of any preceding or followingembodiment, further comprising: an impedance measurement circuit coupledto an output of the stimulator; wherein said instructions, when executedby the processor, further perform steps comprising: (iv) measuring anelectrode-tissue impedance; and (v) adaptively adjusting a compliancevoltage of the stimulator as a function of a known stimulation intensityand the measured electrode-tissue.

35. The system, apparatus or method of any preceding or followingembodiment, wherein said instructions, when executed by the processor,further perform steps comprising: (vi) measuring conductivity betweenany two electrodes to determine if a short circuit has formed betweenelectrodes.

36. The system, apparatus or method of any preceding or followingembodiment, wherein said instructions, when executed by the processor,further perform steps comprising: (vi) monitoring a reparation rate ofthe patient from the measured electrode-tissue impedance.

37. The system, apparatus or method of any preceding or followingembodiment, wherein measuring an electrode-tissue impedance comprisesinjecting a sinusoidal or square current into the target tissue andmeasuring an evoked electrode bio-potential.

38. The system, apparatus or method of any preceding or followingembodiment, further comprising: a battery coupled to the stimulator; andwherein the stimulator comprises a power management circuit configuredto generate both high negative and positive supply voltages from thebattery.

39. The system, apparatus or method of any preceding or followingembodiment, wherein the power management circuit comprises: a firstDC-DC power converter that is configured to produce a first voltage fromthe battery; a second DC-DC power converter that is configured toproduce a second voltage; and a third DC-DC power converter thatgenerates positive and negative high compliance voltages from the firstand second voltages.

40. The system, apparatus or method of any preceding or followingembodiment, wherein the delivered stimuli are configured to mimic thenature electrophysiological signals, including one or more of: EMG, EGG,ECG, action potentials, and local-field potentials.

41. An implantable apparatus for stimulating tissue, comprising: animplantable coil; a power and stimulator module connected to theimplantable coil; a voltage stimulus electrode connected to the powerand stimulator module; a reverse telemetry module connected to theimplantable coil; a sensor connected to the reverse telemetry module;and a recording electrode connected to the sensor; wherein theimplantable coil is configured to couple an external device via awireless inductive coupling such that the power and stimulator modulereceives power and commands from the external device to apply a stimulusvoltage at a treatment location in a body tissue through the voltagestimulus electrode; wherein the sensor is configured to receive one ormore of a stimulus intensity applied by the stimulator module and aphysiological signal received from the body tissue; and wherein thephysiological signal is transmitted to the external device throughwireless inductive coupling.

42. A system for stimulating tissue, comprising: (a) an implantableapparatus; (b) an external device; (c) the implantable apparatuscomprising: (i) an implantable coil/antenna; (ii) a power and stimulatormodule connected to the implantable coil/antenna; (iii) a voltagestimulus electrode connected to the power and stimulator module; (iv) areverse telemetry module connected to the implantable coil/antenna; (v)a sensor connected to the reverse telemetry module; and (vi) a recordingelectrode connected to the sensor; (vii) a battery powering the device);(d) the external device comprising: (i) an external power coil; (ii) apower transmitter connected to the external power coil and configured tosend a power signal to said implantable coil; and (iii) a controllerconnected to the external power coil and configured to controlstimulation parameters and process reverse telemetry of the implantableapparatus.

43. The system of any preceding embodiment: wherein the implantableapparatus is configured to couple to the external device via a wirelessinductive coupling such that the power and stimulator module receivespower and commands from the external device to apply a stimulus voltageat a treatment location in a body tissue through the voltage stimuluselectrode; and wherein the sensor is configured to receive one or moreof a stimulus intensity applied by the stimulator module and aphysiological signal received from the body tissue.

44. The system, apparatus or method of any preceding or followingembodiment: wherein the wireless inductive coupling comprises amodulated power signal; and wherein transmitted data is inserted at theend of the power signal.

45. The system, apparatus or method of any preceding or followingembodiment, wherein the stimulus voltage is configured by modifying abase/gate voltage of a transistor of an output stage of the power andstimulator module

46. The system, apparatus or method of any preceding or followingembodiment, wherein the commands from the external device comprises astimulation command sent using the pulse waveform.

47. A method for treating post-operative ileus, comprising: installingthe disposable implant of any of the preceding embodiments at atreatment location of a gastrointestinal (GI) tract of a patient; andapplying an electrical stimulation at the treatment location at or neara vagus nerve ending to reduce a level of tumor necrosis factor (TNF)associate with the GI tract.

48. A method treating GI dysmotility and inflammation, comprisinginstalling the implant of any of the preceding embodiments at atreatment location of a gastrointestinal (GI) tract or vagus nerve andits branches of a patient; and applying an electrical stimulation at thetreatment location at or near a vagus nerve ending to reduce a level oftumor necrosis factor (TNF) associate with the GI tract or activatingsmooth muscle activities.

As used herein, the singular terms “a,” “an,” and “the” may includeplural referents unless the context clearly dictates otherwise.Reference to an object in the singular is not intended to mean “one andonly one” unless explicitly so stated, but rather “one or more.”

As used herein, the term “set” refers to a collection of one or moreobjects. Thus, for example, a set of objects can include a single objector multiple objects.

As used herein, the terms “substantially” and “about” are used todescribe and account for small variations. When used in conjunction withan event or circumstance, the terms can refer to instances in which theevent or circumstance occurs precisely as well as instances in which theevent or circumstance occurs to a close approximation. When used inconjunction with a numerical value, the terms can refer to a range ofvariation of less than or equal to ±10% of that numerical value, such asless than or equal to ±5%, less than or equal to ±4%, less than or equalto ±3%, less than or equal to ±2%, less than or equal to ±1%, less thanor equal to ±0.5%, less than or equal to ±0.1%, or less than or equal to±0.05%. For example, “substantially” aligned can refer to a range ofangular variation of less than or equal to ±10°, such as less than orequal to ±5°, less than or equal to ±4°, less than or equal to ±3°, lessthan or equal to ±2°, less than or equal to ±1°, less than or equal to±0.5°, less than or equal to ±0.1°, or less than or equal to ±0.05°.

Additionally, amounts, ratios, and other numerical values may sometimesbe presented herein in a range format. It is to be understood that suchrange format is used for convenience and brevity and should beunderstood flexibly to include numerical values explicitly specified aslimits of a range, but also to include all individual numerical valuesor sub-ranges encompassed within that range as if each numerical valueand sub-range is explicitly specified. For example, a ratio in the rangeof about 1 to about 200 should be understood to include the explicitlyrecited limits of about 1 and about 200, but also to include individualratios such as about 2, about 3, and about 4, and sub-ranges such asabout 10 to about 50, about 20 to about 100, and so forth.

Although the description herein contains many details, these should notbe construed as limiting the scope of the disclosure but as merelyproviding illustrations of some of the presently preferred embodiments.Therefore, it will be appreciated that the scope of the disclosure fullyencompasses other embodiments which may become obvious to those skilledin the art.

All structural and functional equivalents to the elements of thedisclosed embodiments that are known to those of ordinary skill in theart are expressly incorporated herein by reference and are intended tobe encompassed by the present claims. Furthermore, no element,component, or method step in the present disclosure is intended to bededicated to the public regardless of whether the element, component, ormethod step is explicitly recited in the claims. No claim element hereinis to be construed as a “means plus function” element unless the elementis expressly recited using the phrase “means for”. No claim elementherein is to be construed as a “step plus function” element unless theelement is expressly recited using the phrase “step for”.

What is claimed is:
 1. An implantable apparatus for installation at atreatment location in a gastrointestinal (GI) tract or at a vagus nerve,the implantable apparatus comprising: (a) a capsule configured forencapsulating a flexible substrate housing a plurality of electrodesdisposed in an electrode array; (b) a system-on-chip (SoC) coupled tothe flexible substrate; (c) passive and/or active components coupled tothe SoC; (d) wherein the SoC and/or the active components incorporate aprocessor and a non-transitory memory storing instructions executable bythe processor, the instructions comprising: (i) delivering, by at leastone electrode of the electrode array, a waveform comprising: (A) aperiodic stimulus of high-intensity pulses for stimulating the targetarea; and (B) a low-intensity stimulus comprising a short pulse insertedwithin the periodic stimulus that is used to monitor tissue impedanceduring a contraction or a relaxation of GI smooth muscle; (ii)determining the patient's physiological status based on the tissueimpedance, wherein the tissue impedance is derived by measuring theelectrode overpotential evoked by the low-intensity stimulus; (iii)adjusting the periodic stimulus based on the patient's physiologicalstatus; and (iv) wherein the waveform comprising the periodic stimulusis configured for restoring GI motility and reducing inflammatoryresponses in the GI tract.
 2. The apparatus of claim 1, furthercomprising: a printed circuit board (PCB) antenna coupled to the SoC,the PCB antenna configured to receive signals from an external devicefor wireless activation of the electrode array and recording of signalsfrom the electrode array; wherein the SoC is disposed between the PCBantenna and the flexible substrate.
 3. The apparatus of claim 2, whereinthe PCB antenna acts as an interposer between the SoC and a batteryconfigured to power the apparatus.
 4. The apparatus of claim 2, whereinthe flexible substrate wraps around the SoC and PCB antenna.
 5. Theapparatus of claim 1, wherein all or a portion of the apparatus isencapsulated in a biocompatible material.
 6. The apparatus of claim 1,wherein the flexible substrate comprises a plurality of suture holes foranchoring the apparatus within the GI tract via an absorbable suture. 7.The apparatus of claim 1, wherein said instructions, when executed bythe processor, further perform steps comprising: delivering a secondlow-intensity stimulus via a second electrode in the electrode arrayseparate from a first electrode in the electrode array, the firstelectrode generating the first low-intensity stimulus; and measuring aGI propagation wave during the smooth muscle contraction/relaxation. 8.The apparatus of claim 1, wherein the low-intensity stimulus pulse isinserted between a group of at least two high-intensity stimulus pulses.9. The apparatus of claim 1, wherein the SoC is positioned on one sideof the flexible substrate so that the specified openings disposedthrough the flexible substrate align with conductive pads of the SoC.10. The apparatus of claim 1, wherein the electrode array is configuredas a cuff electrode for nerve stimulation and recording.
 11. Theapparatus of claim 1, wherein the apparatus further records at least oneof pH value, pressure, and transit time to determine a patient'sphysiological status.
 12. A method for restoring GI motility andreducing inflammatory responses in the GI tract using an implantableapparatus configured to be installed at a treatment location in agastrointestinal (GI) tract or at a vagus nerve, comprising: (a)delivering a waveform by at least one electrode within a capsuleencapsulating an electrode array coupled to a system on a chip (SoC) andpassive and/or active components, wherein the waveform is generated by aprocessor within said SoC and/or active components and comprises: (i) aperiodic stimulus of high intensity pulses configured for stimulating atarget area; and (ii) a low intensity stimulus comprising a short pulseconfigured for determining tissue impedance during a contraction or arelaxation of GI smooth muscle, with said low intensity stimulusinserted within the periodic stimulus; (b) determining by the processorassociated with one or more of the SoC and the active and / or passivecomponents, physiological status of a patient based on tissue impedance;(c) adjusting the periodic stimulus based on the patient's physiologicalstatus; and (d) delivering, by at least one electrode, the waveformcomprising the adjusted periodic stimulus.
 13. The method of claim 12,further comprising: wirelessly recording the GI motility by measuringone or more of the electrode-tissue impedance, GI pH value, and transittime.
 14. The method of claim 12, further comprising: applying anelectrical stimulation at the treatment location at or near a vagusnerve ending to reduce a level of tumor necrosis factor (TNF) associatewith the GI tract.
 15. The method of claim 12, wherein the stimulationpulse waveform is generated via one of more commands sent wirelessly tothe implant from a device external to the patient.
 16. The method ofclaim 12, wherein the tissue impedance is derived by measuring theelectrode overpotential evoked by the low-intensity stimulus.
 17. Themethod of claim 12, the method further comprising; delivering a secondlow-intensity stimulus via a second electrode in the electrode arrayseparate from a first electrode in the electrode array, the firstelectrode generating the first low-intensity stimulus; and measuring aGI propagation wave during the smooth muscle contraction/relaxation. 18.The apparatus of claim 12, wherein the low-intensity stimulus pulse isinserted between a group of high intensity stimulus pulses.
 19. Themethod of claim 12, wherein the method is used to provide treatment forpost-operative ileus (POI).
 20. The method of claim 12, wherein theperiodic stimulus of high intensity pulses is configured to mimicnatural signals such as EMG, EGG, ECG, action potentials, or local-fieldpotentials.